Recently, accompanying with the increased living standard, modernization of living style and aging of society, incidence of diabetes is also kept increasing on a yearly basic all over the world, of which the situation is especially obvious in developing countries. Diabetes has become the third major chronic non-communicable disease next to malignant tumors, cardio-cerebrovascular diseases, and constituted the major causes to death and disability. As reported in WHO report of 1997 that by that time there are 135 millions of people suffering from diabetes and 175 millions are expected to be reached by 2000. In China, a recent report shows that incidence of diabetes in the population of age over 20 is 3.21%. A preliminary estimation shows that there are at least 20 millions of diabetes patients in China nowadays, in which over 95% of them are type 2 diabetes patients. From 1987 to 1992, the annual outlay for direct or indirect uses in diabetes in United State increased from 1 billion to 92 billion US Dollars. In China, the outlay for treatment of diabetes is also increasing at an incredible speed. According to a related statistical analysis reported in 1993 that up to 2.2 billions dollars were spend on the treatment of diabetes at that time, in which neither the cost for the treatment of diabetes complications, outlay for out-hospital treatments and health care nor indirect loss in social economy were included.
Type 2 diabetes can be controlled by moderation of dietary intake, exercise and regulation of the blood-glucose level with medication. Commonly employed medication includes insulin, sulphonylurea, biguanide as well as Glitazone compounds. These compounds help only in promoting the blood-glucose level back to the normal level while unable to recover the impairments, especially to kidney, cardiovascular system, optical or nervous system caused by diabetes complications. These complications are closely associated with the increased mortality caused by diabetes. The major side effects inherent in the first generation of diabetic medications include low in blood-glucose level, increase in body-weight and dropsy. The acting mechanisms of these medications maybe different, however, none of them is able to protect the insulin-secreting β-cell, thereby, the in vivo blood glucose metabolism and incretion regulation cannot be maintained in normal condition. In most cases, consecutive use of a single medicine renders it no longer effective, which gives rise to the application of combined drug treatment. Since diabetes patients take blood pressure-lowering and cholesterol reducing drugs simultaneously during treatment, the long-term effect of this treatment is not stable. Therefore, development of new medications to cooperate with current medications for the regulation of blood glucose level, and to achieve the objects in protecting and recovering the functionality of β-cell as well as adjusting incretion in response to food intake would result in a great improvement in diabetic treatment.
Investigation of Glucagon-like peptide-1 (GLP-1) receptor agonist is a likely topic. Investigation and development in this field may open a new chapter in the treatment of type 2 diabetes. Glucagon-like peptide-1 was firstly discovered in 1984, which is a kind of intestinal secretion hormones. If type 2 diabetics were injected with this hormone, their blood glucose level can be adjusted to a normal level (Nathan, D M, et al. Diabetes Care 1992; 15:270-6; Zander, M, et al. Lancet 2002; 359:824-30). It was reported that action of Glucagon-like peptide and receptor agonist thereof is mainly caused by insulin secretion induced by activating the Glucagon-like peptide 1 receptor on the surface of the pancreas β-cell. Since this effect depends on the in vivo blood glucose level, fatal hypoglycemic shock caused by the extremely low blood glucose level even in the presence of Glucagon-like peptide and receptor agonist thereof would not occur like the traditional medication does. More particularly, when the in vivo blood glucose level is higher than 6 mmol/L, GLP-1 remarkably stimulates secretion of insulin, whereas when the in vivo blood glucose level reaches the normal level, the stimulation discontinue. Also, this type of agonist stimulates the proliferation of pancreas β-cell of rodent (rat) and also enhances the action of β-cell tissue. The function that allows the recovery of the pancreas β-cell opens up prospects for the treatment of type 2 diabetes by at least delaying the onset of type 1 diabetes from type 2 diabetes. Meanwhile the Glucagon-like peptide and receptor agonist thereof is able to inhibit the secretion of glucagon, and thereby make it possible to reduce the output of blood glucose from liver. More importantly, this type of agonist reduces the dietary intake by inhibiting the gastrointestinal peristalsis and gastric emptying, thereby reduces the body weight and also helps in controlling the body weight of type 2 diabetics.